Background: Detection of mutations in the mitochondrial DNA (mtDNA) is usually limited to common mutations and the transfer RNA genes. However, mutations in other mtDNA regions can be an important cause of oxidative phosphorylation (OXPHOS) disease as well.
Objective: To investigate whether regions in the mtDNA are preferentially mutated in patients with OXPHOS disease.
Methods: Screening of the mtDNA for heteroplasmic mutations was performed by denaturing high-performance liquid chromatography analysis of 116 patients with OXPHOS disease but without the common mtDNA mutations.
Results: An mtDNA sequence variant was detected in 15 patients, 5 of which were present in the ND5 gene. One sequence variant was new and three were known, one of which was found twice. The novel sequence variant m.13511A-->T occurred in a patient with a Leigh-like syndrome. The known mutation m.13513G-->A, associated with mitochondrial encephalomyopathy lactic acidosis and stroke-like syndrome (MELAS) and MELAS/Leigh/Leber hereditary optic neuropathy overlap syndrome, was found in a relatively low percentage in two patients from two different families, one with a MELAS/Leigh phenotype and one with a MELAS/chronic progressive external ophthalmoplegia phenotype. The known mutation m.13042G-->A, detected previously in a patient with a MELAS/myoclonic epilepsy, ragged red fibres phenotype and in a family with a prevalent ocular phenotype, was now found in a patient with a Leigh-like phenotype. The sequence variant m.12622G-->A was reported once in a control database as a polymorphism, but is reported in this paper as heteroplasmic in three brothers, all with infantile encephalopathy (Leigh syndrome) fatal within the first 15 days of life. Therefore, a causal relationship between the presence of this sequence variant and the onset of mitochondrial disease cannot be entirely excluded at this moment.
Conclusions: Mutation screening of the ND5 gene is advised for routine diagnostics of patients with OXPHOS disease, especially for those with MELAS- and Leigh-like syndrome with a complex I deficiency.